Method of treating hyperparathyroidism

ABSTRACT

A very safe therapeutic composition having a sufficient curative effect on hyperparathyroidism of a patient subjected to artificial dialysis, which composition contains as the active ingredient at least one member selected from γ-linoleic acid, dihomo-γ-linolenic and derivatives thereof.

This application is a 371 of PCT/JP94/01729 filed Oct. 14, 1994.

TECHNICAL FIELD

The present invention relates to a therapeutic composition forsuppressing hypersecretion of parathyroid hormone due tohyperparathyroidism of patients subjected to artificial dialysis.

BACKGROUND ART

The recent development of hemodialytic therapy has now greatly reduceddeath caused directly by chronic renal failure. Suitable therapy forchronic and renal failure has made it possible to live for another 20year or longer. Accordingly, it has become extremely important toimprove the quality of life (hereinafter referred to as QOL) of patients(that is, to let patients live an ordinary life without being physicallyhandicapped or socially isolated. Therefore, at present, it is desirableto take measures against the complications of chronic renal failure fromwhich patients may suffer while living for a long period of time andalso undertake suitable therapeutic means for ensuring the patients'early rehabilitation in society.

Chronic renal failure exhibits a decrease in the number of nephronsirrespective of the type of renal disorder. The extended decrease in thenumber of nephrons results in the loss of renal function, whichnecessitates artificial dialysis. Renal depression due to a decrease inthe number of nephrons causes a decrease in serum Ca, a decrease in theproduction of active vitamin D, elevation of the serum Ca set-point atwhich the secretion of parathyroid hormone (hereinafter referred to asPTH) is set to be suppressed, a decrease in the number ofparathyroid-activated vitamin D receptors, the metabolic disorderinvolving phosphorus, etc., causing hypersecretion of PTH that may befollowed by secondary hyperparathyroidism.

PTH is indispensable for the regulation of the metabolism of calcium andphosphorus, while having a great influence on the stable maintenance ofbone. Hypersecretion of PTH acts on bone, thereby causing fibrousosteitis. It is said that PTH is one of uremic substances which causeanemia, organic ulcers, central nervous neuropathy, itching,hyperlipemia, etc. and it is a significant factor in the presentation ofthe symptoms of renal osteodystrophy which is a severe complication forpatients subjected to artificial dialysis. Many patients who have oncesuffered from the disorder of renal osteodystrophy are difficult tocure, and the disorder noticeably lowers with the QOL for patientssubjected to artificial dialysis.

It is said that most patients with light renal failure suffer fromsecondary hyperparathyroidism. The frequency and the degree of thecomplication increase in patients who are subjected to artificialdialysis for a long period of time. Therefore, it is necessary toprevent the complication in the early stages of renal failure.

To cure secondary hyperparathyroidism, for example, activated vitamin Dpreparations are administrated to patients with hypocalcemia or thosewith insufficiency of vitamin D production. However, such preparationsinvolve harmful side effects in that they often cause hypercalcemia andectopic calcification. Pulse therapy may be administered to patientsresistant to activated vitamin D preparations. However, pulse therapy isproblematic in that it may cause hypometabolic turnover osteitis, etc.,in addition to the above-mentioned disadvantages. In order to lower theserum Ca set-point at which the secretion of PTH is set to besuppressed, activated vitamin D preparations and calcium preparationsmay be employed, which, however, are still problematic for the abovereasons. On the other hand, aluminum hydroxide is a chemical that shouldnot be administered to patients with hyperphosphatemia caused by themetabolic disorder of phosphorus, who are subjected to artificialdialysis. Therefore, in place of this, calcium carbonate or calciumacetate preparations are administered to them. However, because of poorphosphorus adsorbability, calcium preparations must be administered inlarge quantities, resulting in a high risk of hypercalcemia. Low-proteindietary cure may also be employed with the limitation of phosphorus.However, low-protein diets often bring about negative results oftrophopathy and hypercatabolism. Surgical treatment of an enucleatingparathyroid gland may be employed, which, however, brings about seriousmental and physical strains on patients.

As mentioned hereinabove, the conventional therapeutic means forhyperparathyroidism are all problematic. In particular, for patientssubjected to artificial dialysis for a long period of time, even thecombinations of such means produce unsatisfactory therapeutic effects atpresent.

DISCLOSURE OF THE INVENTION

The present invention has been attained from the above-mentionedviewpoints, and its object is to provide a therapeutic composition forhyperparathyroidism of patients subjected to artificial dialysis, whichcomposition exhibits a sufficient curative effect without having anynegative influence such as harmful side effects and can produce goodresults with regard to QOL.

The present inventors have assiduously studied in order to attain theabove-mentioned object and, as a result, have found that ω-6 unsaturatedfatty acids can significantly depress the hypersecretion of PTH causedby the hyperparathyroidism of patients subjected to artificial dialysis.On the basis of this finding, we have achieved the present invention.

The present invention provides a therapeutic composition forhyperparathyroidism of a patient subjected to artificial dialysis,comprising one or more selected from γ-linolenic acid,dihomo-γ-linolenic acid and derivatives thereof.

The present invention is described in detail hereinunder.

ω-6 unsaturated fatty acids such as γ-linolenic acid, dihomo-γ-linolenicacid, etc. which are used in the present invention, are known asindispensable fatty acids, and it is known that these and theirderivatives (hereinafter referred to as "γ-linolenic acid, etc.") havevarious physiological activities. However, it was entirely unknown thatthese are effective on hyperparathyroidism of patients subjected toartificial dialysis, which effect we have found for the first time.

γ-linolenic acid, etc. to be used in the present invention are fattyacids indispensable to human bodies, and these are safe to patients witha dietary cure such as those subjected to artificial dialysis and canadministrated to them without anxiety.

γ-linolenic acid, etc. can be obtained from oils and fats whichoriginate from mold of the genera Mucor, Mortierella, Rizopus, etc.,plants such as evening primrose, borage, etc. and also algae such asSpirulina, etc. Extracts from these may be used directly or after havingbeen purified. In addition, γ-linolenic acid, etc. can also be obtainedby chemical synthesis, and commercially-available products can also beused.

Derivatives of the above-mentioned γ-linolenic acid anddihomo-γ-linolenic acid include esters.

The form of the therapeutic composition of the present invention forhyperparathyroidism of patients subjected to artificial dialysis is notspecifically defined. For example, one selected from γ-linolenic acid,dihomo-γ-linolenic acid and derivatives thereof, or a mixture of two ormore of these, or an extract to be obtained from oils and fats such asthose of the above-mentioned mold, plants, etc. is mixed with one ormore of ordinary, pharmaceutically-acceptable harmless vehicles,carriers, excipients, binders, preservatives, stabilizers, flavorings,etc., and formed into internal preparations such as tablets, granules,capsules, liquid preparations, etc.; suppositories; vaginalpreparations; external preparations such as ointments, creams, lotions,etc.; and injections such as sterilized solutions, suspensions, etc.These can be formulated in accordance with known techniques.

For example, one or more of the above-mentioned γ-linolenic acid, etc.may be formulated with a binder such as gelatin, etc., a vehicle such ascrystalline cellulose, etc., an excipient such as potato starch, sodiumalginate, etc., a sweetener such as lactose, sucrose, etc., and madeinto powders, tablets, pills or granules. To prepare capsules, a mixtureof γ-linolenic acid, etc. and other oils and fats is encapsulated intosoft gelatin capsules, hard gelatin capsules, etc., in accordance withknown methods. In addition, cyclodextrin clathrates comprisingcyclodextrin and γ-linolenic acid, etc. can also be prepared by knownmethods. To prepare external preparations, vaseline, paraffin, oils andfats, lanolin, etc. are usable as a base.

The above-mentioned γ-linolenic acid, etc. can be combined with ω-3unsaturated fatty acids such as α-linolenic acid, eicosapentaenoic acid,docosahexaenoic acid, etc., ω-5 unsaturated fatty acids such asmyristoleic acid, etc., ω-7 unsaturated fatty acids such as palmitoleicacid, etc., ω-9 unsaturated fatty acids such as oleic acid, ercylicacid, etc.; and saturated fatty acids such as lauric acid, myristicacid, etc., in any desired proportions. In order to prevent theoxidation of γ-linolenic acid, etc., antioxidants such as vitamin E,ascorbyl palmitate, ascorbyl stearate, etc. may be added thereto.

The dose of γ-linolenic acid, dihomo-γ-linolenic acid or its derivativeis not specifically defined. However, if too much of it is administered,the patient is apt to have loose bowels. The dose shall be suitablydetermined, depending on the age, the medical history and the conditionof the patient as well as the type of the disorder, etc. To attain theintended effects for the treatment of hyperparathyroidism, the activeingredient may be administered thereto in an amount of from 50 to 600mg/day, preferably from 100 to 450 mg/day.

BEST MODES FOR CARRYING OUT THE INVENTION

Examples of the present invention are described hereinunder.

PRODUCTION EXAMPLE 1 Capsules

235 parts by weight of oil or fat containing about 22% by weight ofγ-linolenic acid was mixed with 65 parts by weight of vitamin E (TM-70G,produced by Tama Biochemical Co.) by an ordinary method and encapsulatedin gelatin capsules (Football-type No. 5, produced by Fuji Capsule Co.)to produce capsules each containing γ-linolenic acid of 50 mg/capsule.

The oil or fat containing γ-linolenic acid used herein was extractedaccording to the method described in Japanese Patent ApplicationLaid-Open No. 63-283589 (1988). Briefly, cultured cells of Mucorcircinelloides HUT 1121 (FERM P-9359) were subjected to n-hexaneextraction to obtain oil or fat containing γ-linolenic acid.

EXAMPLE Evaluation of Therapeutic Composition of the Invention

The capsules prepared in the above-mentioned Production Example wereadministered to four patients subjected to artificial dialysis, whosuffer from hyperparathyroidism and have medical histories ofhemodialytic treatment shown in Table 1 below, at 7 capsules/day (4capsules after breakfast and 3 capsules after the evening meal each day)which corresponds to 350 mg of γ-linolenic acid per day. Theadministration was started on the same day for the four patients. Forpatients Nos. 1 to 3, administration was continued for 3 months. Then,their data were measured with Allegro Intact PTH kits (produced byNippon Mediphysics Co.) and are shown in Table 2. For patient No. 4,administration was continued for 3 months and thereafter 3 capsules/day(corresponding to 150 mg of γ-linolenic acid per day) were continuouslyadministered after breakfast for 5 months further. Data were thenmeasured with a PTH kit "Yamasa" (produced by Yamasa Shoyu Co.) and areshown in Table 3. The PTH data of the four patients were periodicallymeasured. Their PTH data before and after the administration are shownbelow along with the months counted on the basis of the start ofadministration.

                  TABLE 1                                                         ______________________________________                                        Background of Patients                                                                                   Medical History of Hemo-                           Patient                    dialytic Treatment (at the                         No.      Sex     Age       start of the administration)                       ______________________________________                                        1        Female  44         1 year and 6 months                               2        Female  64         1 year and 2 months                               3        Female  42        10 years and 11 months                             4        Male    46         2 years and 9 months                              ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        PTH Data (measured with Allegro Intact PTH                                    kit - normal value: 11 to 54 pg/ml)                                           Patient     3 Months Before                                                                           3 Months                                              No.         Administration                                                                            Administration                                        ______________________________________                                        1           295         153                                                   2           300         69                                                    3           816         427                                                   ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        PTH Data (measured with PTH Kit "Yamasa"                                      normal value: 160 to 520 pg/ml)                                               Patient No. 4                                                                 ______________________________________                                        Before Administration                                                         13 months before  14,000                                                      12 months before  14,000                                                      10 months before  17,000                                                       7 months before  17,000                                                       4 months before  19,000                                                       1 months before  22,000                                                      Administration                                                                 2 months after   22,000                                                       5 months after   14,000                                                       8 months after   12,000                                                      ______________________________________                                    

From the results in Table 2 and Table 3, it is evident that the PTHvalues of the four patients who are subjected to artificial dialysis andto whom the therapeutic composition for hyperparathyroidism of thepresent invention was administered all declined after administration.From these data, it is obvious that the composition of the presentinvention is efficacious against hyperparathyroidism. Before and afteradministration, no particular medical treatment was administered to thepatients. No abnormal changes were found in their periodically measuredclinical examination data. The safety of the composition of the presentinvention was thus confirmed.

INDUSTRIAL APPLICABILITY

The therapeutic composition of the present invention forhyperparathyroidism of patients who are subjected to artificial dialysisexhibits a marked suppressive effect on the hypersecretion of PTH causedby hyperparathyroidism, and is excellent in terms of safety.

What is claimed is:
 1. A method for treating hyperparathyroidism ofpatients suffering from hyperparathyroidism associated with renaldisorder, comprising administering to said patients at least one ω-6unsaturated fatty acid composition selected from the group consisting ofγ-linolenic acid, dihomo-γ-linolenic acid and derivatives having ω-6unsaturated fatty acid structures thereof in an amount sufficient forsuppressing the hypersecretion of parathyroid hormone of said patients.2. A method according to claim 3, wherein the amount of said at leastone ω-6 unsaturated fatty acid composition administered to said patientsis in the range of from 50 mg/day to 600 mg/day per patient.